Abstract CD48 is a member of the SLAM/CD2 family of leukocyte cell surface regulatory molecules whose gene is located within the lupus-associated Sle1b region of mouse chromosome 1. C57BL/6 (B6) mice with genetic ablation of CD48 (B6.CD48-/-) develop autoimmunity with severe glomerulonephritis (CD48GN) that is reminiscent of human systemic lupus erythematosus. In addition to chronic kidney disease, features of the B6.CD48-/- phenotype include splenomegaly, hypergammaglobulinemia and autoantibody production. This novel model of GN will be used to measure the relative contributions of renal-specific and leukocyte-specific CD48 expression to the onset and progression of immune complex nephritis. In contrast to the lupus-like B6.CD48-/- animals, BALB/c mice with genetic ablation of CD48 (BALB.CD48-/-) have no autoimmune traits, indicating that background gene(s) unique to the different mouse strains modulate the effect of CD48 deficiency. CD48-null F1 progeny of B6.CD48-/- x BALB.CD48-/- parents are also non-autoimmune, suggesting that background gene effects are recessive. Preliminary data further demonstrate that approximately 40% of CD48-null N2 pups from F1.CD48-/- x B6.CD48-/- backcrosses produce anti-DNA antibodies, substantiating a Mendelian inheritance of this trait. A series of CD48-null mice with differing combinations of B6 and BALB/c genomic loci will be phenotyped with respect to GN and autoantibody production and will be genotyped using single nucleotide polymorphism (SNP) based genome-wide scans. Quantitative trait linkage (QTL) analysis will be used to identify B6-specific modifier(s) of CD48GN and associated disease traits. Murine genetic polymorphisms may ultimately implicate human polymorphisms that can predict renal involvement in systemic autoimmune disease. Project Narrative End stage renal disease is a large and ever growing medical problem, predicted to outstrip current medical resources within the next two decades. Approximately 20% of pediatric and 10% of adult chronic renal patients have some form of autoimmune nephritis. Lupus nephritis is one example that occurs in approximately 1/500-5000 individuals worldwide and accounts for substantial renal morbidity and mortality, in part because diagnosis often occurs after kidney disease begins and the treatments are themselves fairly harmful and not always effective. This project proposes to study a new mouse model of lupus nephritis to understand how the protein called CD48 regulates disease and to discover additional genes that modify disease severity, with the long term goals of developing more sensitive clinical tests to diagnose kidney conditions while they are still mild and also to help design safer medical therapies.